Effects of a pure antiestrogen and progesterone on estrogen-mediated alterations of blood flow and progesterone receptor expression in the aorta of ovariectomized rabbits.
There is ample evidence from epidemiological studies that estrogen-replacement therapy protects postmenopausal women against cardiovascular disease. One explanation for this beneficial effect could be the improvement of blood flow under estrogen therapy. By using ultrasound and Doppler color flow mapping we demonstrated in the aorta of ovariectomized rabbits a significant dose-dependent increase in blood flow after treatment with 17beta-estradiol. An increase in blood flow was already observed within 1 h of estradiol treatment and lasted until the end of a 14-day treatment phase. Progesterone did not attenuate the effects of 17beta-estradiol on aortic blood flow. The pure estrogen receptor antagonist ZM 182780, however, dose-dependently reversed the effect of 17beta-estradiol on blood flow after the 14-day treatment phase, but was not able to antagonize the rapid 17beta-estradiol effect on blood flow after 1 h. After killing the animals mRNA and protein expression of the progesterone receptor (PR), a known estrogen-responsive gene in classic target organs, were examined. Analogous to the blood flow results the PR mRNA level increased dose-dependently after 17beta-estradiol treatment, whereas ZM 182780 was able to reverse this effect. Immunohistochemical localization of PR in the aortic wall revealed an increase in immunoreactivity in fibroblasts of the adventitia after 17beta-estradiol treatment. ZM 182780, and to a lesser degree progesterone, reversed the 17beta-estradiol-induced increase in PR immunoreactivity. PR immunoreactivity was further detected in endothelial and smooth muscle cells, but the various hormonal treatments had no discernible effect on the PR mRNA level in these cellular compartments. Our findings in the aorta of OVX rabbits suggest that (a) 17beta-estradiol exhibits a rapid effect on arterial tone, (b) the pure estrogen receptor antagonist ZM 182780 inhibits the 17beta-estradiol effect on blood flow and PR mRNA and (c) progesterone does not attenuate the beneficial effect of estrogens on arterial tone.
Hegele-Hartung
C
C
Research Laboratories of the Schering AG, Berlin, Germany. christa.hegelehartung@Schering.de
Fritzemeier
K H
KH
Diel
P
P
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D007150:Immunohistochemistry; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011980:Receptors, Progesterone / Q000235:genetics*; D012039:Regional Blood Flow / Q000187:drug effects
D004965:Estrogen Antagonists; D004967:Estrogens; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D000077267:Fulvestrant; D011374:Progesterone; D004958:Estradiol